Abstract

Despite remarkable advances in research and clinical management, metastatic breast cancer remains incurable and causes most deaths in human breast cancer patients due to the unavailability of specific, targeted therapy. Therefore, identification of functional metastasis genes and further unveiling the molecular mechanisms underlying metastasis process remains the top priority in cancer research field. In recent years, much evidence supports the notion that epithelial-mesenchymal transition (EMT), a developmental program involved in a variety of tissue remodeling events, contributes to cancer cell plasticity and to the invasive potential of transformed epithelial cells. However, the legitimacy of EMT is still challenged by disagreements among pathologists who dismiss EMT as a fallacy.

Utilizing a cross-species expression profiling strategy which combined microarray technique and model cell lines, we identified 22 up-regulated and 12 down-regulated genes as an essential genetic program in both human and mouse highly-metastatic model cell lines. About half of the gene candidates are novel and their roles in metastasis have not been reported. We randomly selected four genes and investigated their roles in metastatic characteristics including EMT program and cell migration and invasion. Overexpression of GCNT2 gene (an up-regulated gene candidate) not only led to a marked increase of cell migration and invasion, but also led to marked alterations in epithelial-mesenchymal transition (EMT) program. Ectopic expression of MAPK12 (another upregulated gene) only changed the EMT program but has no effect on cell migration and invasion. Overexpression of IRX5 (a down-regulated gene) not only led to a marked decrease of cell migration and invasion in vitro, but also a modulation of EMT program. However, expression of PHLDA3 (another down-regulated gene) only affect the cell migration and invasion, but has no effect on EMT program. These results highlight the feasibility of the cross-species expression profiling approach as a strategy to identify gene targets that are involved in breast cancer metastasis. The results of the functional studies for randomly selected genes further suggest that this multigenic program is consisted of different genes that play various roles in controlling EMT and/or Cell migration and invasion ability. Further studies are needed to investigate the effect of these novel gene candidates on metastasis in vivo and as therapeutic targets for treatment of breast cancer metastasis.